Ischemic myocardium undergoes virtually no histological changes when reperfused in the early phase of ischemia; however, when ischemia is sustained and reperfusion occurs during the course of necrosis, reperfusion injuries such as reperfusion-induced arrhythmia, no-reflow phenomenon and myocardial necrosis, which are mainly caused by Ca2+ overload, are observed. If these reperfusion injuries could be suppressed to be minimal, it would be expected that such prevention would lead to an improved mortality or improved post-infarction cardiac function.
The NHE on the cell membrane is an ion transporter which controls the pH inside a cell by permitting a Na+ influx into the cell and pumping H+ out of the cell, and increased activity of the NHE is believed to cause the Ca2+ overload during ischemic reperfusion. It is therefore conceived that an NHE inhibitor suppresses the Ca2+ overload, thereby suppressing the ventricular fibrillation caused by reperfusion-induced arrhythmia and suppressing expansion of myocardial necrosis.
Furthermore, it is also suggested that NHE is involved in ischemia or ischemic reperfusion injury in various organs such as brain, liver and kidney in addition to the heart, as well as in hypertension, angina pectoris, cardiac hypertrophy, diabetes mellitus, diseases caused by proliferability of cells, or diseases caused by vascular endothelial disorder. Therefore, an NHE inhibitor is expected to be effective in suppressing these diseases or disorders, and is considered to be useful as a therapeutic agent or prophylactic agent of these diseases or disorders.
Amiloride, a K+ sparing diuretic represented by the formula shown below, is a pyrazine derivative having acylguanidine. This derivative has NHE inhibitory effect, and is also reported to exhibit antiarrhythmic effect (Non-Patent Document 1). However, the antiarrhythmic effect of amiloride is weak, and also, amiloride has antihypertensive effect and salt excreting effect, which are rather considered as side effects that are undesirable for the treatment of arrhythmia.

As a derivative which is not associated with the salt excreting effect, but has NHE inhibitory effect and antiarrhythmic effect, a benzoylguanidine derivative (Non-Patent Document 2, Patent Documents 1 and 2), an indolylguanidine derivative (Patent Document 3), an aminoguanidinehydrazone derivative (Patent Document 4), and a cycloalka[b]pyridine derivative (Patent Document 5) have been respectively reported.
In recent years, it has been reported that when the NHE inhibitor passes through the blood brain barrier and arrives at the brain, it manifests characteristic neurotoxicity which commonly appears in specific areas (Non-Patent Document 3). It is also reported that a NHE1 gene-deficient mouse displays severe ataxia, and neuropathy that is specific to cerebellum, vestibular nucleus and cochlear nucleus (Non-Patent Document 4). Therefore, the neurotoxicity of conventional NHE inhibitors has potential to induce various neuropathies. Accordingly, development of an NHE inhibitor which does not affect neurons is desired.
In Patent Document 6, introducing a —SO3H group (sulfo group), a —PO3H2 group or the like to the NHE inhibitors via various crosslinking groups has been suggested as a method of reducing the effect of the NHE inhibitors on the nervous system, particularly on the central nervous system, and specifically, the case of an indolylguanidine derivative is disclosed. However, since no specific data is presented for the effect of such introduction, the effectiveness of the introduction has been not proved for all conventional NHE inhibitors.
In fact, the inventors of the present invention have synthesized and investigated a variety of derivatives, and found that depending on the combination of the substituent and the NHE inhibitor as a nucleus, in some cases the NHE inhibitory effect has been significantly attenuated, or in some cases the derivative has been metabolized immediately after administration to be converted to the original NHE inhibitor, or in some cases, even the derivative itself has been exhibited an action on the central nervous system. Thus, such derivatives are not necessarily effective in reducing toxicity to the central nervous system.
[Patent Document 1] Japanese Patent Application Laid-open No. 5-339228
[Patent Document 2] Japanese Patent Application Laid-open No. 8-073427
[Patent Document 3] Japanese Patent Application Laid-open No. 8-208602
[Patent Document 4] Japanese Unexamined Patent Application No. 2000-191641
[Patent Document 5] International Patent Application Publication WO 98/39300
[Patent Document 6] International Patent Application Publication 01/044186
[Non-Patent Document 1] Circulation, Vol. 79, p. 1257-1263 (1989)
[Non-Patent Document 2] Journal of Molecular Cell Cardiology, Vol. 24 (suppl. I), S. 92 (1992)
[Non-Patent Document 3] European Journal of Pharmacology, Vol. 459, p. 151-158 (2003)
[Non-Patent Document 4] Cell, Vol. 91, p. 139-148 (1997)